Lipin1 is a key factor for the maturation and maintenance of adipocytes in the regulatory network with CCAAT/enhancer-binding protein alpha and peroxisome proliferator-activated receptor gamma 2.
Lipin1 expression was induced at a late stage of differentiation of 3T3-L1 preadipocytes and maintained at high levels in mature adipocytes. Knockdown of expression of lipin1 by small interfering RNA in 3T3-L1 preadipocytes almost completely inhibited differentiation into adipocytes, whereas overexpression of lipin1 accelerated adipocyte differentiation, demonstrating that lipin1 is required for adipocyte differentiation. In mature adipocytes, transfection of lipin1-small interfering RNA decreased the expression of adipocyte functional genes, indicating the involvement of lipin1 in the maintenance of adipocyte function. Lipin1 increases the transcription-activating function of peroxisome proliferator-activated receptor gamma(2) (PPAR gamma(2)) via direct physical interaction, whereas lipin1 did not affect the function of other adipocyte-related transcription factors such as C/EBP alpha, liver X-activated receptor alpha, or sterol regulatory element binding protein 1c. In mature adipocytes, lipin1 was specifically recruited to the PPAR gamma-response elements of the phosphoenolpyruvate carboxykinase gene, an adipocyte-specific gene. C/EBP alpha up-regulates lipin1 transcription by directly binding to the lipin1 promoter. Based on the existence of a positive feedback loop between C/EBP alpha and PPAR gamma(2), we propose that lipin1 functions as an amplifier of the network between these factors, resulting in the maintenance of high levels of the specific gene expression that are required for adipogenesis and mature adipocyte functions.
Koh
Yoo-Kyung
YK
Department of Biochemistry and Molecular Biology, Brain Korea 21 Project for Medical Science, Institute of Genetic Science, Center for Chronic Metabolic Disease Research, Yonsei University College of Medicine, Seoul 120-752, Korea.
Lee
Min-Young
MY
Kim
Jae-Woo
JW
Kim
Minji
M
Moon
Jong-Seok
JS
Lee
Yoo-Jung
YJ
Ahn
Yong-Ho
YH
Kim
Kyung-Sup
KS
D041721:3T3-L1 Cells; D017667:Adipocytes / Q000378:metabolism; D000818:Animals; D022763:CCAAT-Enhancer-Binding Protein-alpha / Q000378:metabolism*; D002454:Cell Differentiation; D004268:DNA-Binding Proteins / Q000378:metabolism; D000071518:Liver X Receptors; D051379:Mice; D008954:Models, Biological; D041681:NIH 3T3 Cells; D009687:Nuclear Proteins / Q000737:chemistry*; D009841:Oligonucleotides / Q000737:chemistry; D057093:Orphan Nuclear Receptors; D047495:PPAR gamma / Q000378:metabolism*; D010711:Phosphatidate Phosphatase; D010957:Plasmids / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism; D051780:Sterol Regulatory Element Binding Protein 1 / Q000378:metabolism
D022763:CCAAT-Enhancer-Binding Protein-alpha; D004268:DNA-Binding Proteins; D000071518:Liver X Receptors; D009687:Nuclear Proteins; D009841:Oligonucleotides; D057093:Orphan Nuclear Receptors; D047495:PPAR gamma; D034741:RNA, Small Interfering; D018160:Receptors, Cytoplasmic and Nuclear; D051780:Sterol Regulatory Element Binding Protein 1; C418978:Lpin1 protein, mouse; D010711:Phosphatidate Phosphatase